title: IGF-1-overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1alpha/CXCR4 signaling to promote myocardial repair.
abstract: We hypothesized that mesenchymal stem cells (MSCs) overexpressing insulin-like growth factor (IGF)-1 showed improved survival and engraftment in the infarcted heart and promoted stem cell recruitment through paracrine release of stromal cell-derived factor (SDF)-1alpha. Rat bone marrow-derived MSCs were used as nontransduced ((Norm)MSCs) or transduced with adenoviral-null vector ((Null)MSCs) or vector encoding for IGF-1 ((IGF-1)MSCs). (IGF-1)MSCs secreted higher IGF-1 until 12 days of observation (P<0.001 versus (Null)MSCs). Molecular studies revealed activation of phosphoinositide 3-kinase, Akt, and Bcl.xL and inhibition of glycogen synthase kinase 3beta besides release of SDF-1alpha in parallel with IGF-1 expression in (IGF-1)MSCs. For in vivo studies, 70 muL of DMEM without cells (group 1) or containing 1.5x10(6) (Null)MSCs (group 2) or (IGF-1)MSCs (group 3) were implanted intramyocardially in a female rat model of permanent coronary artery occlusion. One week later, immunoblot on rat heart tissue (n=4 per group) showed elevated myocardial IGF-1 and phospho-Akt in group 3 and higher survival of (IGF-1)MSCs (P<0.06 versus (Null)MSCs) (n=6 per group). SDF-1alpha was increased in group 3 animal hearts (20-fold versus group 2), with massive mobilization and homing of ckit(+), MDR1(+), CD31(+), and CD34(+) cells into the infarcted heart. Infarction size was significantly reduced in cell transplanted groups compared with the control. Confocal imaging after immunostaining for myosin heavy chain, actinin, connexin-43, and von Willebrand factor VIII showed extensive angiomyogenesis in the infarcted heart. Indices of left ventricular function, including ejection fraction and fractional shortening, were improved in group 3 as compared with group 1 (P<0.05). In conclusion, the strategy of IGF-1 transgene expression induced massive stem cell mobilization via SDF-1alpha signaling and culminated in extensive angiomyogenesis in the infarcted heart.
authors.affiliation: Department of Pathology and Laboratory of Medicine, 231 Albert Sabin Way, University of Cincinnati, Cincinnati, OH 45267-0529, USA.
authors.forename: Husnain Kh
authors.initials: HKh
authors.lastname: Haider
authors.forename: Shujia
authors.initials: S
authors.lastname: Jiang
authors.forename: Niagara M
authors.initials: NM
authors.lastname: Idris
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000502:physiology*; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology*; D009203:Myocardial Infarction / Q000601:surgery / Q000628:therapy*; D051381:Rats; D055647:Rats, Transgenic; D019718:Receptors, CXCR4 / Q000502:physiology; D015398:Signal Transduction; D014945:Wound Healing / Q000502:physiology*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D006133:Growth Substances; D019718:Receptors, CXCR4; D007334:Insulin-Like Growth Factor I